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Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides

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  1. Degradable dendritic nanogels as carriers for antimicrobial peptides

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  2. Multiscale modeling of innate immune receptors: Endotoxin recognition and regulation by host defense peptides

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  4. Variability in the diagnosis of surgical-site infections after full-thickness skin grafting: an international survey

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  5. Prevalence of chronic wounds in the general population: systematic review and meta-analysis of observational studies

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  • Rathi Saravanan
  • Daniel A Holdbrook
  • Jitka Petrlova
  • Shalini Singh
  • Nils A Berglund
  • Yeu Khai Choong
  • Sven Kjellström
  • Peter J Bond
  • Martin Malmsten
  • Artur Schmidtchen
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Thrombin-derived C-terminal peptides (TCPs) of about 2 kDa are present in wounds, where they exert anti-endotoxic functions. Employing a combination of nuclear magnetic resonance spectroscopy (NMR), biophysical, mass spectrometry and cellular studies combined with in silico multiscale modelling, we here determine the bound conformation of HVF18 (HVFRLKKWIQKVIDQFGE), a TCP generated by neutrophil elastase, in complex with bacterial lipopolysaccharide (LPS) and define a previously undisclosed interaction between TCPs and human CD14. Further, we show that TCPs bind to the LPS-binding hydrophobic pocket of CD14 and identify the peptide region crucial for TCP interaction with LPS and CD14. Taken together, our results demonstrate the role of structural transitions in LPS complex formation and CD14 interaction, providing a molecular explanation for the previously observed therapeutic effects of TCPs in experimental models of bacterial sepsis and endotoxin shock.

Original languageEnglish
JournalNature Communications
Volume9
Issue number1
Pages (from-to)2762
ISSN2041-1723
DOIs
Publication statusPublished - 17 Jul 2018

    Research areas

  • Amino Acid Sequence, Antimicrobial Cationic Peptides/chemistry, Binding Sites, Escherichia coli/genetics, Humans, Hydrophobic and Hydrophilic Interactions, Leukocyte Elastase/chemistry, Lipopolysaccharide Receptors/chemistry, Lipopolysaccharides/chemistry, Neutralization Tests, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, THP-1 Cells, Thrombin/chemistry

ID: 56331444